This application is a request for the continuation of a senior scientist award that has been funded for 5 years. At least 75% of the applicant's time will be directed to research, and the rest to research related activities in teaching and service. He will also continue to be the PI of the NIDA funded institutional training grant. He also will continue to mentor graduate students, post-doctoral fellows and young faculty members. The applicant will continue to serve in a leadership role in "The Friends of NIDA", an organization that he helped to develop for science advocacy among scientists and non-scientists. The everyday operation of this organization will be handled by a hired firm so as not to detract from the applicant's own research projects described in this application. The research to be carried out during the next five year cycle will be a continuation of funded research the applicant has been awarded by NIDA. He serves as the principal investigator of an R01 grant entitled "Enkephalins, Neuropharmacology and Abuse Potential" and of a project entitled "Cellular systems in the acute and chronic effects of cannabinoids" in a program project grant. The research proposed in this application is a combination of those projects. A common theme that flows through these projects is to identify the steps in signal transduction that are involved in the acute effects and tolerance that develops to these two families of abused drugs. We have demonstrated that protein kinase A (PKA) and protein kinase C (PKC) both reverse 8 fold morphine tolerance to the analgesic, hypothermia and changes in Straub tail in mice. We have also shown that one needs to inhibit both PKA and PKC to reverse a 45-fold tolerance occurring 3-days after morphine pellet implantation. However, a resistance to tolerance reversal by PKC and PKA inhibitors develops progressively over 18 days of chronic morphine exposure, indicating the activation of alternative pathways. PKI-tide a specific inhibitor of PKA reversed 3-day morphine tolerance and reversed the increase in PKA levels found in the spinal cord of morphine tolerant mice. The work described in this application is designed to continue to elucidate whether a correlation exists between reversal of morphine tolerance and an alteration of PKA or PKC activity in selected areas of the brain. It has also been shown in our laboratories that PKA inhibitors also reverse the pronounced tolerance produced by delta-9 THC. At the present time, we are in the process of examining the effect of long term treatment with cannabinoids on levels of PKA in brain regions. In other studies we have demonstrated cross tolerance between the exogenous cannabinoid, delta-9 THC and the endogenous cannabinoid, anandamide and synthetic more stable analogs of anandamide. Work described in this application will be directed toward elucidating whether changes in brain PKA and/or PKC in brain occur after chronic treatment with delta-9 THC and whether similar effects occur with chronic treatment with stable analogs of anandamide. Cross tolerance between the two classes of cannabinoids will also be evaluated.